Metastatic hormone refractory prostate cancer, one of many carcinomas, such as cancer of the breast, liver, pancreas, bladder, lung, skin, colon, and the like, responds poorly to chemotherapy because of its slow rate of replication. It accounts for about 40,000 deaths annually. There has been no satisfactory treatment for metastatic, hormone refractory prostate cancer. Patients with the disease die with diffuse pain, obstructive renal failure, and bone marrow failure due to replacement by the tumor. Treatment of carcinoma needs an agent which is effective independently of the rate of cell division or the ability to interfere with DNA or RNA metabolism.
Rhodamine-123 (Rh-123) is such an agent. It preferentially localizes in the mitochondria of malignant living cells because of a difference in the plasma membrane potential of normal and malignant cells, together with the positive charge on this lipophilic molecule. Therefore, Rh-123 is selectively toxic for carcinoma cells. In 1986, I reported the effect of a saline suspension of Rh-123 on the transplantable rat prostate tumor R3327-H (Dunning). The Rh-123 solution was administered subcutaneously every other day at a dosage of 15 mg/kg body weight. There was significant destructive alteration of the acinar cells with disruption of the cells from the basement membrane, destruction of the cytoplasm, as well as vacuolization and change in fibroblast shape and density.
In 1990, I reported the highly malignant, androgen-independent transplantable tumor designated P-A III to be highly sensitive to Rh-123 dissolved in DMSO. The Rh-123 treatment of the tumor resulted in significant destruction of tumor cells, with no toxicity noted in normal cells. Injection of tumor remnants into untreated susceptible Lobund-Wistar (L-W) rats produced no tumor growth.
In terms of a process, my invention provides a method for treating a patient with carcinoma by administration of Rhodamine-123 (Rh-123) in an amount sufficient to effect in vivo destruction of the cancer cells. Preferably, the Rh-123 is administered intravenously in a solution of ethyl alcohol and water. Preferably, the solution includes dextrose, and each dose of Rh-123 is administered to the patient by infusion with between about 10 and about 250 ml of the Rh-123 solution over a period between about 15 minutes and about 4 hours. The concentration of Rh-123 in the infused solution can be any convenient amount, but normally is between about 1 and about 20 mg/ml.
In another embodiment, the Rh-123 is administered orally either as a liquid, or as a pill, such as a tablet or capsule. Preferably, the pill releases the Rh-123 over an extended period of time, say, 2 to 24 hours, to avoid toxicity.
Preferably, the patient is treated with intermittent doses of Rh-123, which are generally increased from about 0.5 mg of Rh-123 per kg of patient weight up to about 30 mg per kg of patient weight, or until toxicity is observed, whichever comes first. In the case of prostate cancer, the treatment is continued until the level of prostate specific antigen (PSA) or prostate specific acid phosphatase in the patient's blood decreases significantly from the level prevailing in the patient just prior to treatment in accordance with this invention.
The Federal Food and Drug Administration (FDA) prefers that the administration of therapeutic agents be reported on the base of the surface area of the patient, which is calculated in accordance with the weight and height of the patient. For a typical prostate cancer patient, 1 kg of patient weight is equivalent to about 0.025 m2 of surface area.
In terms of composition of matter, the invention provides a solution for treating a patient with carcinoma. The solution comprises ethyl alcohol and Rh-123 dissolved in water. Preferably, the solution also includes about 5% by weight of a sugar, such as dextrose or glucose, susceptible to metabolic assimilation.
The invention also provides a stock solution for preparing an administration solution used in treating carcinoma. The stock solution comprises Rh-123 dissolved in ethyl alcohol (preferably 95% ethyl alcohol and 5% water). The concentration of the Rh-123 in the stock solution is between about 5 and about 25 mg per ml.
These and other aspects of the invention will be more fully understood from the following description and the accompanying drawings.